1. Field of the Invention
The present invention relates to a method of preparing [123I]Iodooctyl fenbufen amide and application.
2. The Prior Arts
Non steroid anti inflammatory drugs (NSAIDs) have been well recognized for their anti inflammatory efficacy. NSAIDs are including many types of drugs, such as aspirin, naproxen, diclofenac sodium, ibuprofen and fenbufen. Chronic inflammation is associated with an increased risk of cancer for individuals with inflammatory bowel diseases. Hence, cancer prevention by these NSAIDs is a perceivable concept.
The inflammatory mechanism is mainly associated with the inflammatory lipids which are catalyzed by a key enzyme, cyclooxygenase (COX). COX converts arachidonic acid (AA) to prostaglandin H2 (PGH2) via two sequential steps, and PGH2 is the precursor of the series-2 prostanoids. Therefore, the cyclooxygenase plays a central role in a series of inflammatory signals. COX contains two active sites: a heme with peroxidase activity, responsible for the reduction of PGG2 (Prostaglandins G2) to PGH2, and a cyclooxygenase site, where arachidonic acid is converted into the hydroperoxy endoperoxide prostaglandin G2 (PGG2). The reaction proceeds through H atom abstraction from arachidonic acid by a tyrosine radical generated by the peroxidase active site. Two O2 molecules then react with the arachidonic acid radical, yielding PGG2. Initial oxidation to PGG2 by cyclooxygenase and subsequent reduction to an unstable endoperoxide intermediate PGH2 by peroxidase. The two reactions displace in spatially distinct but mechanistically coupled active sites. The cyclooxygenase active site is located at the end of a long hydrophobic channel that is broad near the membrane-binding domain (the lobby) and narrows as it extends toward the interior of the protein. The peroxidase active site is located on the surface of the protein near the heme cofactor. In many tumors, higher prostaglandin levels are upregulated by COX.
Three types of COXs have been reported: COX-1, COX-2, and COX-3 in which (1) COX-1 is functioned as a house-keeping enzyme and constitutively expressed in most tissue types; (2) COX-2 is a highly inducible enzyme under physiological conditions; and (3) COX-3 is a splice mutation of COX-1, which retains intron one and has a frameshift mutation; thus some prefer the name COX-b or COX-1 variant (COX-1v). COX-1 is present in the most human tissue, such as gastric mucosa, kidney and platelet. COX-2 is mainly present in the macrophages and synovial cells, COX-2 causes inflammation reaction when the body hurt. NSAIDs can inhibit the activity of COX, and also block the formation of prostaglandin, prostacyclin and thromboxane to have pain-relieving effects and have the effect of reducing inflammation. Besides, the long-term uptake of NSAIDs has the effect of cancer prevention, but the uptake of non-specific anti-COX-1 inhibitors always accompanies with adverse side effects such as gastrointestinal toxicity. Therefore, specific anti COX-2 inhibitors were developed to overcome this side effect. However, prolonged use of COX-2 inhibitors encounters other side effects such as the cardiovascular events, it needs to limit the use. Due to the complexity of COX mechanism such as dual functionality of the enzyme and the close coupling of the two active sites, novel agents with unique inhibition is still under development.
Imaging of inflammation as well as tumor progression attracts a great attention recently. Being a diagnostic imaging probe for PET (Positron Emission Tomography) or SPECT (Single Photon Emission Computer Tomography) application, the cytotoxicity is not a serious concern since only very low dosage (lower than 1/100 of the therapeutic dose) is administered by an individual within a short period. Various PET and SPECT tracers based on the structural characteristics of COX-2 and COX-1 specific inhibitors have been developed in the past decades. However, only rare radiopharmaceuticals have been successfully applied in imaging of inflammatory events. The probable cause has been attributed to the instability of COX-2 or due to the very low absolute amount of COX-2 overexpression for detection.
In present research, the radiolabeled [18F]-N-(4-fluorobutyl)ethacrynic amide ([18F]FBuEA) only shows the image of cold spot in rat liver tumor lesion, the physician or medical technologist can not observe the level of the radioactivity accumulated because only the image of hot spot can be observed the radiation intensity and the level of organ inflammation or lesion.